Autoimmune diseases - rilonacept

The body produces a variety of cytokine proteins, which either promote or inhibit inflammation and, in some cases, can do either depending on the conditions.

Targeting the proinflammatory cytokines, such as tumour necrosis factor, interferon-gamma and the interleukins 1, 2, 6, 15, 18 and 18, provides potential therapeutic routes to treating a number of inflammatory conditions. In particular, IL-1 and IL-6 are believed to be involved in conditions such as inflammatory bowel disease, rheumatoid arthritis, congestive heart failure and even cancer.

Several agents that block the activity of IL-1 have already been developed, including receptor antagonists, antibodies that attack various points on its activity cascade, and even soluble IL-1 receptors. However, many of these have limited use, often because they need to be administered every day because of high clearance rates, and there is also the danger of inducing immune responses, or even enhancing its activity instead of reducing it.

An alternative strategy is to use a cytokine trap. These are fusion molecules between the Fc region of immunoglobulin G1 and extracellular domains of molecules on the IL-1 pathway. Regeneron has developed rilonacept, which acts in this way, and the extracellular domain components are IL-1RacP and IL-1RI. It has a high binding affinity for both IL-1β and IL-1α, and has been shown to be a potent inhibitor of IL-1 activity both in vitro and in vivo.¹ It is being investigated as a treatment for several immune mediated diseases.

One condition for which it is being evaluated is rheumatoid arthritis. In a randomised, double blind, single dose placebo-controlled Phase I trial to evaluate its safety and efficacy, 107 patients with rheumatoid arthritis were given 50, 100, 200, 400 or 800 µg/kg subcutaneously for six weeks.² They were also allowed to receive prednisone or methotrexate. Side-effect profiles were similar across patients who received placebo and rilonacept, with the most common being a stinging at the injection site. No antibodies against the drug were detected in any of the patients, and many of those given the highest dose experienced an improvement in their symptoms.

A 12 week randomised, multicentre placebo-controlled Phase II trial was also carried out in 201 patients with moderate to severe rheumatoid arthritis who had failed treatment with at least one other disease modifying antirheumatic drug.³ Subjects were given 25, 50 or 100mg of the drug or placebo once a week by subcutaneous injection. It was well tolerated, and significant improvements were seen in disease activity score in those patients given the highest dose compared with placebo, even after just one week of treatment.

It is also being evaluated as a treatment for familial cold autoinflammatory syndrome and Muckle Wells syndrome.⁴ In a randomised, double blind, placebo-controlled Phase III study, 47 patients with FCAS/MWS were given 160mg of the drug a week in a six week treatment comparison phase and a second phase of single blind rilonabant, followed by a nine-week randomised withdrawal comparison phase. In the six-week comparison phase, substantial decreases of signs and symptoms were seen, and during the withdrawal phase, those given placebo saw their disease activity gradually increase again.